Lesions of the orbitofrontal but not medial prefrontal cortex disrupt conditioned reinforcement in primates

Abstract

The ventromedial prefrontal cortex (PFC) is implicated in affective and motivated behaviors. Damage to this region, which includes the orbitofrontal cortex as well as ventral sectors of medial PFC, causes profound changes in emotional and social behavior, including impairments in certain aspects of decision making. One reinforcement mechanism that may well contribute to these behaviors is conditioned reinforcement, whereby previously neutral stimuli in the environment, by virtue of their association with primary rewards, take on reinforcing value and come to support instrumental action. Conditioned reinforcers are powerful determinants of behavior and can maintain responding over protracted periods of time in the absence of and potentially in conflict with primary reinforcers. It has already been shown that conditioned reinforcement is dependent on the amygdala, and because the amygdala projects to both the orbitofrontal cortex and the medial PFC, the present study determined whether conditioned reinforcement was also dependent on one or the other of these prefrontal regions. Comparison of the behavioral effects of selective excitotoxic lesions of the PFC in the common marmoset revealed that orbitofrontal but not medial PFC lesions disrupted two distinct measures of conditioned reinforcement: (1) acquisition of a new response and (2) sensitivity to conditioned stimulus omission on a second-order schedule. In contrast, the orbitofrontal lesion did not affect sensitivity to primary reinforcement as measured by responding on a progressive-ratio schedule and a home cage consumption test. Together, these findings demonstrate the critical and specific involvement of the orbitofrontal cortex but not the medial PFC in conditioned reinforcement.

Figure 1.

Schematic diagrams of a series of coronal sections through the frontal lobe of the marmoset illustrating the site of the lesion of the medial PFC and orbitofrontal lesion of group 1 (G.1) in experiments 1, 2, and 4 and group 2 (G.2) in experiments 3 and 4. The different levels of shading, ranging from solid black to pale gray, represent the areas of cortex that were damaged in all monkeys, in all monkeys but one, etc., to just one monkey, respectively. The distribution of granular (G), dysgranular (dG), and agranular (aG) regions of cortex within the frontal lobes of the marmoset are illustrated in the series of coronal sections depicted in the inset. The frontal pole is granular throughout. The shaded regions on each coronal section within the inset represent the regions on the orbital surface and the medial wall that were the targets for the orbitofrontal and medial PFC lesions, respectively.

Figure 2.

Low-power (A, C, E, G) and high-power (B, D, F, H) photomicrographs of cresyl fast violet-stained coronal sections through rostral (A, B, E, F) and intermediate (C, D, G, H) levels of the frontal lobe taken from a representative marmoset from the medial PFC (A-D)- and orbitofrontal (E-H)-lesioned groups. The extensive cell loss in the lesioned areas is in stark contrast to the dense layering of neurons seen in the adjacent intact areas. In addition, the loss of orbitofrontal tissue in the orbitofrontal-lesioned monkey (E, G) is in contrast to the intact orbitofrontal cortex in the medial PFC-lesioned monkey (A, C) and vice versa. The arrows in A, C, E, and G and the dotted lines in B, D, F, and H mark the border(s) of the lesion. The asterisks mark the same position in A, C, E, and G as they do in B, D, F, and H, respectively.

Figure 3.

A, Mean ± SEM number of responses at each level of the second-order schedule both before and after surgery for control animals (n = 5), animals with orbitofrontal lesions (n = 5), and animals with medial PFC lesions (n = 4). Numbers in parentheses indicate the numbers of animals remaining in each group at each level of the schedule. FRx(FRy:S) denotes y number of responses before presentation of the CS (S) and x number of CSs before receiving primary reinforcement. Thus, 5(7:S) reflects the level at which seven responses are required before presentation of a CS and five such CSs must be gained, and thus a total of 35 responses made, before obtaining primary reinforcement. B, The ratio of responses on the CS omission and post-CS omission phases relative to the pre-CS omission phase [e.g., CS omission/(CS omission + pre-CS omission)] for the control, orbitofrontal, and medial PFC-lesioned groups. A score of 0.5 indicates that responding was equivalent to the pre-CS omission phase. Each symbol represents the ratio score of an individual animal. The asterisk indicates that the response ratio for the CS omission phase in the orbitofrontal-lesioned group was significantly greater than that of the control group at p < 0.05.

Figure 4.

The cumulative mean ± SEM volume of liquid reward consumed in the home cage across three consecutive 20 min time bins represented by the open, light gray, and dark gray sectors of the histograms, respectively, in control (n = 5), orbitofrontal-lesioned (n = 5), and medial PFC-lesioned (n = 4) groups. Three different concentrations of reward were tested on different days: normal (i.e., the concentration used as reward in the test apparatus), weak (i.e., a concentration half as strong as normal), and strong (i.e., a concentration twice as strong as normal).

Figure 5.

A, Mean ± SEM number of responses at each level of the progressive-ratio schedule for the control (n = 4), orbitofrontal-lesioned (n = 3), and medial PFC-lesioned (n = 5) groups. Numbers on the x-axis reflect the total numbers of responses required at each level to receive primary reinforcement. Numbers in parentheses indicate the numbers of animals remaining in each group at each level of the schedule. B, The ratio of response rates on the US omission and post-US omission phases relative to the pre-US omission phase [e.g., US omission/(US omission + pre-US omission)] for the control, orbitofrontal, and medial PFC-lesioned groups. A score of 0.5 indicates that responding was equivalent to the pre-US omission phase. Each symbol represents the ratio score of an individual animal.

Figure 6.

Mean ± SEM number of responses to the visual stimulus paired with the CS+ and to the visual stimulus paired with the CS- across the two sessions of acquisition of a new response in control (n = 8), orbitofrontal-lesioned (n = 8), and medial PFC-lesioned (n = 7) groups. Although the control and medial PFC-lesioned groups responded more to the stimulus paired with the CS+ than to the stimulus paired with the CS-, the orbitofrontal-lesioned group did not. Double and single asterisks indicate that responding to the CS+ was significantly greater than responding to the CS- at p < 0.01 and p < 0.05, respectively.